UK-CAB Jan05 Paediatric HIV Care UK-CAB - 28 Jan 2005 HIV i-Base

UK-CAB Jan05 Background 1 Three years after the first descriptions (in 1981) of adult AIDS cases, similar disease characteristics were reported in children Early 80s – most HIV+ children infected by blood transfusion (greatly reduced following the introduction of HIV specific antibody tests in 1985) Since the early 90s the number of vertically infected children increased - approx 1200 in UK Approx 950 HIV+ children in UK now With ARV treatment transmission is now <1%

UK-CAB Jan05 Background 2 In general: HIV progresses more rapidly in children than in adults Very high CD4 compared to adults (CD4%)  More rapid decrease of CD4 cells  Higher viral load at same CD4 count  Impaired growth

UK-CAB Jan05 CD4 % Lymphocytes are white blood cells (B cells and T cells) 2 main types of T-cells: T-4 cells and T-8 cells Absolute CD4 count used to be the product of Total Lymphocytes and percentage that are CD4 (pre 1996, now CD4 cells are counted) The CD4% is the % of T-cells that are CD4 cells HIV-negative : normal = 35-40%

UK-CAB Jan05 CD4 % 1500 >1000>500 no supp>25%>25%>25% Cat mod15-24%15-24%15-24% Cat 3 <750<500<200 severe <15%<15%<15%

UK-CAB Jan05 CD4 % CD4% is useful in adult care - less variability but does not add any information to prediction of risk of illness CD4% is ESSENTIAL in paediatric care

UK-CAB Jan05 However With effect ARV treatment: mortality rates declining from 5.4% in 1995 to 1% in Children have an increased ability to recover from the damage caused by HIV.

UK-CAB Jan05 On HAART Children experience significant CD4 increases – 320 to 650 cells in the first year of treatment (vs adults 100 to 250) - but this dependent on age and limitations of CD4 count more naïve cells than adults Importance of age - ie the younger you are, the more likely to get higher numbers of CD4 cells CD4 can increase to normal or near normal levels even with detectable viral load Some ‘miraculous’ results, though not universally successful

UK-CAB Jan05 How are children different? Different immunology Immature immune system Functioning thymus Higher level and more variation of CD4 cells (this declines with age) Different pattern of HIV RNA Decline of HIV viral load up to 5 years Different metabolism Different absorption rates to adults Different elimination rates Metabolism changing at different ages

UK-CAB Jan05 Log 10 HIV-1 RNA plotted against age with fitted line and 95% CI Log 10 RNA copies/ml Age in years

UK-CAB Jan05 Children’s clinical trials Many questions about treatment for HIV can be answered in adult trials and so it is unnecessary to repeat all trials in children. This has been controversial in the past. (viral load etc) PENTA (Paediatric European Network for Treatment of AIDS) PACTG (Paediatric AIDS Clinical Trials Group)

UK-CAB Jan05 Clinical trials in children Issues –Tolerability and toxicity –When to treat –Choice of endpoints for efficacy Problems –Limited numbers of children (almost all trials underpowered for age) –Limited anti-HIV drugs with paediatric formulations –Need to study pharmacokinetics of agents in different age groups

UK-CAB Jan05 Clinical Trials in Children Focus on questions specific to children Address issues of pharmacokinetics, toxicity and tolerability Multinational collaborations (legal, cultural) Address several questions at a time Different ethical issues (ie recent GSK report in NYC) Close collaboration with adults

UK-CAB Jan05 ARVs used in children NRTIs Abacavir (ABC) - oral solution Didanosine (ddI) - powder for oral solution Lamivudine (3TC) - oral solution Stavudine (d4T) - oral solution Zidovudine (ZDV, AZT) - oral solution Tenofovir - crushed tablets FTC NNRTIs Nevirapine (NVP) - suspension Efavirenz (EFV) - syrup >3 years PIs Nelfinavir (NFV) - powder for oral suspension Lopinavir/r (LPV/r) - oral solution >2 years Ritonavir (RTV) - oral solution Amprenavir (APV) - oral solution >3 years No liquid formulation Indinavir (IDV) - not from Merck Saquinavir (SQV) EIs T children in study but rarely used if other choices available

UK-CAB Jan05 Dosing Paediatric dosing is based on limited data It is liable to change as new information becomes available Use in clinical practice can often differ from doses recommended in licensed SPC

UK-CAB Jan05 Dosing/ PK  Adult doses provide the reference point for paediatric doses  Either body weight or body surface area (BSA) are used to adjust doses  For a ‘typical’ 5 year old a BSA calculated dose could be over 50% greater than one adjusted by weight For AZT this 5 year old would receive a dose of 80mg with a mg/kg adjustment vs a dose of 140mg with a BSA adjustment

UK-CAB Jan05 Calculating BSA Body Surface Area (BSA) can be calculated with the following equation: BSA (m2)=√ (Height (cm) X Weight (kg) /3600)

UK-CAB Jan05 Penta 7 Study Design: A multicentre phase I/II non comparative study of ddI, D4T, NFV in infants < 12 weeks of age, without AIDS. Objectives:To describe the tolerability, toxicity & antiviral activity of early treatment Nelfinavir started at 120 mg/kg/day Increased to 150/kg/day (this represents 5 times the equivalent adult dose!) AT 24 weeks <50 log 10 copies/ml in only 3/12 (25%) This study was stopped by it’s DSMB

UK-CAB Jan05 When to start? PENTA Guidelines Always start ART if Clinical stage C or CD4 <15% 2 Consider ART if Clinical stage B or CD 4 6 log if age 5 log if age over 1 year) 3 Defer ART if Stage N or A disease, and CD4 > 20 %, and, Low VL (<6 log if age < 1year, and <5 log if age over 1 year)

UK-CAB Jan05 Issues to consider when starting therapy in children Parents wishes Likelihood of good long term adherence What formulations could this child take? What PK data are available? What drugs are other family members on?

UK-CAB Jan05 Starting therapy early Advantages  Allow normal development of the immune system  Positive effect on long-term natural history (especially for babies born to treated mothers)  Possibility to clear infection (babies)?  Reset set point after primary infection, if stop Disadvantages  Some children don’t need HAART for many years  Long term effects of ART on QoL  Short and long term toxicity  Getting the right dose!!!  Possibility to develop resistance (inadequate PK, adherence) and reduce future HAART options  Loose HIV specific immune responses (babies)?

UK-CAB Jan05 Early therapy for infants If decide to start early: –Resistance testing at baseline if mother on ART –Choose regimen based on tolerability and PK –Support for adherence –Think about management for toxicity, failure, success If decide to defer: –Monitor clinical, growth, CD4 and HIV RNA –Base decision on rate of change as well as absolutes

UK-CAB Jan05 Practical matters food intake requirements sleep requirements dosage issues with teaspoons / liquids formulation of medications children vomit more easily accidental overdose Pill/liquid burden Ease of administration With/without food Number of times per day Creative use of drug-drug interactions

UK-CAB Jan05 Adherence Particularly difficult issue in children  Dependent both on the child, and on the parent/carer  Dosing schedule - number and size of pills  Taste of liquid or powder formulations  Age of the child  Fears regarding disclosure  Awareness of their diagnosis Adherence support Age appropriate charts etc Pill swallowing lessons G-tubes

UK-CAB Jan05 Pharmacokinetics Definition: ‘The action of drugs in the body, including the processes of absorption, transformation, distribution to tissues, duration of action and elimination. Age dependent Depends on surface area Variability NNRTI’s and PI’s cleared more rapidly in children Dosing in puberty?

UK-CAB Jan05 Changing baseline PK pretermfull1 m1 y3 m6 yAdult body water gastric acid body fat liver function renal

UK-CAB Jan05 Lopinavir Concentrations (Data from Liverpool TDM Service)

UK-CAB Jan05 Nevirapine Concentrations (Data from Liverpool TDM Service)

UK-CAB Jan05 Reasons to consider TDM dose & plasma relationship is unpredictable concentration-effect relationship exists efficacy / toxicity not immediately obvious changing baseline PK practical dosing difficulties Adults Kids Y Y N Y

UK-CAB Jan05 Limitations of TDM Highly dependent on information on time of dose Only reflection of situation before visit) Only one drug in the combination Difficulty taking blood PIs are highly bound to protein; protein levels may vary within and between patients Compartments - only measuring blood plasma Optimal frequency of sampling unknown – example: wk 4, 8, 12, then every 12 weeks

UK-CAB Jan05 Models of care St Mary’s family clinic, London Established in 1993 as family HIV clinic Families can be seen in a single hospital visit Inpatient and outpatient Holistic model - multidisciplinary team including: psychologist, physiotherapist, dietician, specialist health visitor, social worker as well as HIV paediatricians, adult clinician, obstetrician. pharmacist and clinical nurse specialist 85% clinic population from sub-saharan Africa

UK-CAB Jan05 Sophia Children’s Hospital, University of Rotterdam Created in 1997 by group of Dutch paediatricians Multidisciplinary study group Over 40 kids enrolled in a protocol using IDV/ZDV/3TC - all comers ‘Research questions should only be raised when they serve to improve the quality of life with children’ Ronald de Groot

UK-CAB Jan05 Issues for advocates and parents Individuality of any situation Relationship to research from adult care New formulations for pipeline and existing drugs Ethical issues, especially trials Ethical issues relating to PEG tubes Implications of long-term treatment and toxicity

UK-CAB Jan05 Paediatric guidelines PENTA:

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